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1 Malignant Hyperthermia Center, AO Cardarelli, via San Giacomo dei Capri 66, 80131 Napoli, Italy.
2 Telethon Institute. of Genetics and Medicine (TIGEM), via Pietro Castellino 111, 80131 Napoli, Italy
3 Dipartimento di Patologia Generale e Centro di Eccellenza sulle Malattie Cardiovascolari, Seconda Università degli Studi di Napoli, via Luigi De Crecchio 7, 80138 Napoli, Italy.
aAddress correspondence to this author at: Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, via Luigi De Crecchio 7, 80138 Napoli, Italy. Fax 39-081-5665704; e-mail vincenzo.nigro{at}unina2.it.
Background: Malignant hyperthermia (MH) is a fatal autosomal dominant pharmacogenetic disorder characterized by skeletal muscle hypertonicity that causes a sudden increase in body temperature after exposure to common anesthetic agents. The disease is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. To date, at least 42 RYR1 mutations have been described that cause MH and/or central core disease. Because the RYR1 gene is huge, containing 106 exons, molecular tests have focused on the regions that are more frequently mutated. Thus the causative defect has been identified in only a fraction of families as linked to chromosome 19q, whereas in others it remains undetected.
Methods: We used denaturing HPLC (DHPLC) to analyze the RYR1 gene. We set up conditions to scan the 27 exons to identify both known and unknown mutations in critical regions of the protein. For each exon, we analyzed members from 52 families with positive in vitro contracture test results, but without preliminary selection by linkage analysis.
Results: We identified seven different mutations in 11 MH families. Among them, three were novel MH alleles: Arg44Cys, Arg533Cys, and Val2117Leu.
Conclusion: Because of its sensitivity and speed, DHPLC could be the method of choice for the detection of unknown mutations in the RYR1 gene.
The following articles in journals at HighWire Press have cited this article:
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  K. Anderson-Pompa, A. Foster, L. Parker, L. Wilks, and D. J. Cheek Genetics and Susceptibility to Malignant Hyperthermia Crit. Care Nurse, December 1, 2008; 28(6): 32 - 36. [Full Text] [PDF]
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 S. Levano, D. Keller, E. Schobinger, A. Urwyler, and T. Girard Rapid and Accurate Detection of Atypical and Kalow Variants in the Butyrylcholinesterase Gene Using Denaturing High Performance Liquid Chromatography Anesth. Analg., January 1, 2008; 106(1): 147 - 151. [Abstract] [Full Text] [PDF]
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H.-M. Yeh, M.-C. Tsai, Y.-N. Su, R.-C. Shen, J.-J. Hwang, W.-Z. Sun, and L.-P. Lai Denaturing High Performance Liquid Chromatography Screening of Ryanodine Receptor Type 1 Gene in Patients with Malignant Hyperthermia in Taiwan and Identification of a Novel Mutation (Y522C) Anesth. Analg., November 1, 2005; 101(5): 1401 - 1406. [Abstract] [Full Text] [PDF]
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 S. Kobayashi, M. L. Bannister, J. P. Gangopadhyay, T. Hamada, J. Parness, and N. Ikemoto Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor J. Biol. Chem., February 25, 2005; 280(8): 6580 - 6587. [Abstract] [Full Text] [PDF]
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 A. Bagattin, C. Veronese, B. Bauce, W. Wuyts, L. Settimo, A. Nava, A. Rampazzo, and G. A. Danieli Denaturing HPLC-Based Approach for Detecting RYR2 Mutations Involved in Malignant Arrhythmias Clin. Chem., July 1, 2004; 50(7): 1148 - 1155. [Abstract] [Full Text] [PDF]
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